Project Summary/Abstract: Periodontal diseases are associated with the development of systemic conditions including cardiovascular disease, diabetes, and inflammatory bowel disease (IBD). However, the mechanism by which periodontal diseases contribute to the pathogenesis of extra-oral diseases is not fully understood. The long-term goal of this proposal is to unravel the effect of periodontitis on extra-oral disease risk, particularly IBD. The objective of this application is to identify mechanisms by which periodontitis influences the development of intestinal inflammation. Our preliminary data demonstrate that experimental periodontitis in mice results in oral dysbiosis accompanied by the expansion of oral pathobionts. The accumulation of oral pathobionts in turn leads to the generation of oral bacteria-reactive Th17-skewed effector memory CD4+ T (TEM) cells within the oral mucosa. The de novo bacteria-reactive TEM cells that arise in the oral cavity express a gut-homing molecule ?4?7 integrin. Adoptively transferred bacteria-reactive TEM of oral origin subsequently can home to the gut where these cells are activated via gut bacteria and inducing inflammation. It is reported that bacteria-reactive TEM cells accumulate in the intestinal mucosa of IBD patients. These T cells display a Th17 or Th1/Th17 combined phenotype and are considered pathogenic. However, it remains largely unknown about the mechanisms by which these bacteria-reactive pathogenic TEM cells develop. Based on preliminary data, our central hypothesis is that pathogenic TEM cells, arising from periodontal oral infection, transmigrate to the gut where these cells are activated by gut bacteria and contribute to gut inflammation. This hypothesis will be tested by pursuing the following two specific aims: 1) Identify the responsible pathobionts that activate orally-primed T cells in the extra-oral mucosa. Orally-primed TEM cells may cross-react with gut resident bacteria or are activated by ectopically-colonized oral bacteria in the gut; and 2) Assess the contribution of orally-primed TEM cells that drive extra-oral mucosal inflammation. We will examine the impact of the depletion migrant TEM cells on the severity of gut inflammation. The rationale for the proposed research is that, once it is determined how memory T cells arising from oral inflammation are involved in the exacerbation of intestinal inflammation, improved control of oral disease will result in new and innovative ways to treat systemic diseases initiated by oral infection.